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REVIEW

www.nature.com/clinicalpractice/neuro

Drug Insight: new drugs in development


for Parkinsons disease
Carlo Colosimo*, Giovanni Fabbrini and Alfredo Berardelli

INTRODUCTION

S U M M A RY
For many years, levodopa has given most patients with Parkinsons
disease excellent symptomatic benefit. This agent does not slow down the
progression of the disease, however, and it can induce motor fluctuations
and dyskinesias in the long term. The other available antiparkinsonian
agents also have drawbacks, and as a consequence research into
antiparkinsonian drugs is expected to take new and different directions
in the coming years. The most promising approaches include the
development of neuroprotective drugs that are capable of blocking or at
least slowing down the degenerative process that is responsible for cellular
death; restorative strategies intended to restore normal brain function;
more-effective agents for replacing dopamine loss; and symptomatic and
antidyskinetic drugs that act on neurotransmitters other than dopamine
or target brain areas other than the striatum. In this Review, we discuss the
numerous drugs in development that target the primary motor disorder in
Parkinsons disease.
KEYWORDS dopamine, dyskinesias, levodopa, Parkinsons disease

REVIEW CRITERIA
PubMed was searched using Entrez for articles published up to 30 April 2006,
including electronic early release publications. Search terms included Parkinsons
disease and treatment, as well as drugs. The abstracts of retrieved citations
were reviewed and prioritized by relevant content. Full articles were obtained
and references were checked for additional material where appropriate. Abstracts
of the main International Congresses (Movement Disorder Society, American
Academy of Neurology, American Neurological Association, European Federation
of Neurological Societies, and European Neurological Society) were reviewed.
Data available in company websites, clinical trials databases, and the FDA and
European Agency for the Evaluation of Medicinal Products (EMEA) websites
were analyzed. The results of some trials conveyed to the authors by personal
communication were also included.

C Colosimo and G Fabbrini are faculty members at the University


Department of Neurosciences and run the Movement Disorders Clinic, and
A Berardelli is full Professor of Neurology at the Department of Neurosciences
and Neuromed Institute, all at the University of Rome La Sapienza, Italy.
Correspondence
*Department of Neurological Sciences, University of Rome La Sapienza, Viale dellUniversit 30,
I-00185 Rome, Italy
carlo.colosimo@uniroma1.it
Received 9 May 2006 Accepted 24 August 2006
www.nature.com/clinicalpractice
doi:10.1038/ncpneuro0340

600 NATURE CLINICAL PRACTICE NEUROLOGY

The dopamine precursor levodopa gives most


patients with Parkinsons disease (PD) excellent symptomatic benefit, but dopaminergic
therapy has major shortcomings: it neither slows
the progression of the disease nor fully relieves
drug-induced symptoms as PD advances. The
main complications of chronic dopaminergic
therapy are motor fluctuations and levodopainduced dyskinesia (LID), both of which can
affect the quality of life of patients with PD.
Motor response fluctuations, typically accompanied by LID, develop in more than 50% of
all patients treated with levodopa for 5 years or
more.1,2 Although the exact pathophysiology
of these complications remains unclear, they
probably reflect disease progression and striatal
dopamine receptor changes after dopaminergic
denervation and chronic pulsatile exposure to
levodopa.35
Developed as alternative first-line agents,
dopamine agonists usually have a better
pharmacokinetic profile than levodopa and have
overcome somebut not allof levodopas
disadvantages.2 Dopamine agonists administered to primates that have been rendered
parkinsonian by lesioning of the brain with
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) induce less-frequent and less-severe
dyskinesias than levodopa.6,7 Dopamine agonists
can also alleviate parkinsonian symptoms in
previously untreated patients, thereby substantially reducing the incidence of fluctuations and
dyskinesias.8,9 Unfortunately, fewer than 30% of
parkinsonian patients show a good and durable
response to dopamine agonists administered as
monotherapy over a 5-year period.2 Chronic
use of dopamine agonists also leads to frequent
psychiatric side effects, including visual hallucinations, delusions and paranoid psychosis.
Other potentially severe side effects are sudden
sleepiness and compulsive gambling. When
given with levodopa or after priming with
levodopa, dopamine agonists might contribute
to the development of dyskinesias.2 Attempts

NOVEMBER 2006 VOL 2 NO 11


2006 Nature Publishing Group

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